Present medical treatment of shin soreness and other musculo-skeletal inflammation in horses involves mainly administration of nonsteroidal anti-inflammatory drugs (NSAIDs). For example, phenylbutazone has been the definitive drug used in the race horse industry for many years. However, phenylbutazone has a long and unpredictable excretion and, while the pharmacological actions of this drug may be complete within 24 hours, undesirable detection may continue in plasma and urine for long periods after cessation of treatment. This is of importance to animals required to compete drug-free. Furthermore, phenylbutazone has established and widely reported gut toxicity in the horse.
Indomethacin [1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate] has a half-life of 2 to 11 hours which means it must be administered 2 to 3 times daily to be effective [Flower, R. J., Moncado, S., and Vane, J. R., Analgesic-Antipyretics and Anti-Inflammatory Agents: Drugs employed in the treatment of gout. In "The Pharmacological Basis of Therapeutics" (7th Ed., Eds. Gilman, A. G., Goodman, L. S., Rall, T. W., and Murad, F., MacMillan, New York, 1985)].
While it is known that indomethacin has an anti-inflammatory action, it is also known that it causes gastrointestinal reactions in some mammals, e.g. dogs and humans. These reactions include single or multiple ulcerations of the esophagus, stomach and duodenum. Attempts to reduce these gastrointestinal effects have been made by taking the oral drug immediately after meals, with food, milk or antacids, or antiulcer compounds.
NSAIDs also have an analgesic effect which is partly a result of, and partly dissociated from, their anti-inflammatory action. This dissociation varies from drug to drug. Thus, analgesia obtained from phenylbutazone and, to a lesser extent indomethacin, is primarily a result of its anti-inflammatory action.
Certain complexes of indomethacin and divalent metals are known. See Sorenson, J. Med. Chem., 19, 135-148 (1976); ES 448,955 (November 1977); Chemical Abstracts, 89, 375 (abs. no. 186070) (1978); Weser et al., Biochim. Biophys. Acta., 631, 232-245 (1980); Lewis et al., Agents Actions Suppl., 8 (Trace Elem. Pathog. Treat. Inflammation), 339-58 (1981); Romanian 73 044 (Dec. 28, 1982); Romanian 73 045 (Oct. 30, 1982); Sorenson et al., Biol. Trace Elem. Res., 5, 257-273 (1983); Chemical Abstracts, 99, 574 (abs. no. 105123) (1983); Chemical Abstracts, 100, 635 (abs. no. 103177) (1984); Ivancheva et al., Acta Physiol. Pharmacol. Bulgarica, 14, 52-59 (1988); Singla et al., Int'l J. Phamaceutics, 60, 27-33 (1990). Some of these complexes have been reported to have anti-inflammatory, anti-arthritic or analgesic activity. See ES 448,955; Chemical Abstracts, 89, 375 (abs. no. 186070) (1978); Lewis et al., Agents Actions Suppl., 8 (Trace Elem. Pathog. Treat. Inflammation), 339-58 (1981); Romanian 73 044; Romanian 73 045; Chemical Abstracts, 99, 574 (abs. no. 105123) (1983); Chemical Abstracts, 100, 635 (abs. no. 103177) (1984).
In particular, Weser et al., Biochim. Biophys. Acta., 631, 232-245 (1980) teaches copper.sub.2 indomethacin.sub.4 ((CH.sub.3).sub.2 SO).sub.2 complexes. The yield of these complexes obtained by Weser et al. is very poor (2%; see page 233). Also, the presence of the dimethyl sulfoxide in the complexes renders them unsuitable for pharmacological use. These complexes have, consequently, only been laboratory items of no apparent benefit to man or domestic animals. Weser et al. also teaches copper.sub.2 indomethacin.sub.4 (H.sub.2 O).sub.2 complexes, but no method of preparing these complexes is specified.
Okuyama et al., Agents and Actions, 21, 130-144 (1987) reports that copper.sub.2 indomethacin.sub.4 complexes prepared as described in Sorenson, J. Med. Chem., 19, 135-148 (1976) are more effective as analgesics than is indomethacin or morphine in the writhing mouse and adjuvant arthritic rat pain models. Sorenson, J. Med. Chem., 19, 135-148 (1976) reports that these complexes have the formulas copper.sub.2n indomethacin.sub.4n ((CH.sub.3 COCH.sub.3).sub.2n and copper.sub.2n indomethacin.sub.4n (H.sub.2 O).sub.4n (see Table IV) and suggests a binuclear structure for them (see page 141). Sorenson, J. Med. Chem., 19, 135-148 (1976) also reports that the copper.sub.2n indomethacin.sub.4n ((CH.sub.3 COCH.sub.3).sub.2n and copper.sub.2n indomethacin.sub.4n (H.sub.2 O).sub.4n complexes have anti-ulcer activity (see Table IV). See also Sorenson et al., Biol. Trace Elem. Res., 5, 257-273 (1983) which reports that copper.sub.2 indomethacin.sub.4 ((CH.sub.3 COCH.sub.3).sub.2 complexes have anti-ulcer activity. No method for the preparation of the copper.sub.2 indomethacin.sub.4 ((CH.sub.3 COCH.sub.3).sub.2 complexes is taught by Sorenson et al., Biol. Trace Elem. Res., 5, 257-273 (1983) .